19-49665763-T-C

Variant names:

• chr19-49665763-T-C
• rs2304204
• NM_001571.6:c.-141A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001571.6(IRF3):​c.-141A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 1,539,912 control chromosomes in the GnomAD database, including 66,402 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.38 (13454 hom., cov: 32)
  • Exomes 𝑓: 0.27 (52948 hom.)
• Consequence: IRF3 NM_001571.6 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.102
• Publications: 40 publications found

Genes affected

IRF3 (HGNC:6118): (interferon regulatory factor 3) This gene encodes a member of the interferon regulatory transcription factor (IRF) family. The encoded protein is found in an inactive cytoplasmic form that upon serine/threonine phosphorylation forms a complex with CREBBP. This complex translocates to the nucleus and activates the transcription of interferons alpha and beta, as well as other interferon-induced genes. The protein plays an important role in the innate immune response against DNA and RNA viruses. Mutations in this gene are associated with Encephalopathy, acute, infection-induced, herpes-specific, 7. [provided by RefSeq, Sep 2020]

BCL2L12 (HGNC:13787): (BCL2 like 12) This gene encodes a member of a family of proteins containing a Bcl-2 homology domain 2 (BH2). The encoded protein is an anti-apoptotic factor that acts as an inhibitor of caspases 3 and 7 in the cytoplasm. In the nucleus, it binds to the p53 tumor suppressor protein, preventing its association with target genes. Overexpression of this gene has been detected in a number of different cancers. There is a pseudogene for this gene on chromosome 3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.661 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF3	NM_001571.6	c.-141A>G		5_prime_UTR_variant	Exon 1 of 8	ENST00000377139.8	NP_001562.1
BCL2L12	NM_138639.2	c.-313T>C		upstream_gene_variant		ENST00000246784.8	NP_619580.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF3	ENST00000377139.8	c.-141A>G		5_prime_UTR_variant	Exon 1 of 8	1	NM_001571.6	ENSP00000366344.3
BCL2L12	ENST00000246784.8	c.-313T>C		upstream_gene_variant		1	NM_138639.2	ENSP00000246784.4

Frequencies

GnomAD3 genomes AF: 0.380 AC: 57701 AN: 151986 Hom.: 13419 Cov.: 32

Gnomad AFR AF: 0.667

Gnomad AMI AF: 0.363

Gnomad AMR AF: 0.335

Gnomad ASJ AF: 0.245

Gnomad EAS AF: 0.245

Gnomad SAS AF: 0.321

Gnomad FIN AF: 0.230

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.261

Gnomad OTH AF: 0.345

GnomAD4 exome AF: 0.266 AC: 368789 AN: 1387808 Hom.: 52948 Cov.: 31 AF XY: 0.267 AC XY: 181719 AN XY: 681788

African (AFR) AF: 0.683 AC: 21257 AN: 31124

American (AMR) AF: 0.328 AC: 11681 AN: 35596

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 5610 AN: 22488

East Asian (EAS) AF: 0.245 AC: 9468 AN: 38616

South Asian (SAS) AF: 0.327 AC: 25346 AN: 77530

European-Finnish (FIN) AF: 0.234 AC: 11606 AN: 49572

Middle Eastern (MID) AF: 0.404 AC: 1714 AN: 4242

European-Non Finnish (NFE) AF: 0.248 AC: 265695 AN: 1071756

Other (OTH) AF: 0.289 AC: 16412 AN: 56884

GnomAD4 genome AF: 0.380 AC: 57793 AN: 152104 Hom.: 13454 Cov.: 32 AF XY: 0.374 AC XY: 27835 AN XY: 74378

African (AFR) AF: 0.667 AC: 27669 AN: 41464

American (AMR) AF: 0.335 AC: 5120 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 849 AN: 3468

East Asian (EAS) AF: 0.245 AC: 1265 AN: 5162

South Asian (SAS) AF: 0.319 AC: 1538 AN: 4820

European-Finnish (FIN) AF: 0.230 AC: 2438 AN: 10594

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.261 AC: 17733 AN: 67994

Other (OTH) AF: 0.347 AC: 733 AN: 2112

Alfa AF: 0.317 Hom.: 18187

Bravo AF: 0.399

Asia WGS AF: 0.376 AC: 1305 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	8.5
DANN	Benign	0.76
PhyloP100		-0.10
PromoterAI		0.049	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2304204; hg19: chr19-50169020; COSMIC: COSV55863408; COSMIC: COSV55863408;